Pregnancy imprints regulatory memory that sustains anergy to fetal antigen

摘要

成功受孕需要从父亲遗传的胎儿抗原形成有效的耐受机制。这些抗原会引发一个免疫反应，因为它们被母亲的免疫系统认为“不是自身的”。Jared Rowe等人发现，这一点是通过母亲体内针对胎儿抗原的调控性T-细胞的生成实现的。针对胎儿抗原的调控性T-细胞在第二次怀孕期间以加快的速度重新积累，并且可以解释为什么伴侣特定性二次怀孕显示惊厥前期和其他并发症的发病率下降。%Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3~+ regulatory T cells (T_(reg) cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss. In turn, many idiopathic pregnancy complications proposed to originate from disrupted fetal tolerance are associated with blunted maternal T_(reg) expansion. Importantly, however, the antigen specificity and cellular origin of maternal T_(reg) cells that accumulate during gestation remain incompletely defined. Here we show that pregnancy selectively stimulates the accumulation of maternal FOXP3~+ CD4 cells with fetal specificity using tetramer-based enrichment that allows the identification of rare endogenous T cells6. Interestingly, after delivery, fetal-specific T_(reg) cells persist at elevated levels, maintain tolerance to pre-existing fetal antigen, and rapidly re-accumulate during subsequent pregnancy. The accelerated expansion of T_(reg) cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3~+ cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of pre-existing FOXP3~+ cells each contribute to T_(reg) expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3~+ cell ablation. Thus, pregnancy imprints FOXP3~+ CD4 cells that sustain protective regulatory memory to fetal antigen. We anticipate that these findings will spark further investigation on maternal regulatory T-cell specificity that unlocks new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting T_(reg) cell memory.